Use of nanotechnology in medicine has shown exciting prospect for development of novel drug delivery and release system. However, existing nano-drug delivery/release strategies against HIV reservoir have less strength than limitations which restrict their use as a novel drug delivery method to CNS. For example, polymeric nanoparticles such as butyl cyanoacrylate are not ideal for the delivery of polar/ionic compounds and its degradation can produce toxic formaldehyde by-products. Polycationic surface of dendrimers is cytotoxic and associated drug release kinetics is very inconsistent. Micelles and liposomes are very unstable and possess threat of severe leakiness of associated drugs. Even drug-carrying monocytes/macrophages may have inconsistent extravasation across the BBB, and drug delivery from monocytes/macrophages may depend on exocytosis of drug containing intracellular vesicles and intracellular Ca2+ concentrations and pathology-specific responses such as change in temperature, pH, etc. Further, magnetic nanoparticles have been used for MRI imaging purpose where ART has been tagged with specific ligands.
Earlier studies have shown that magnetic nanoparticles (MNP) tagged with AZTTP demonstrated significant inhibition of HIV-1 p24 antigen production in an in-vitro PBMC infection model system compared to free AZTTP, and magnetized monocytes containing AZTTP transmigrated across BBB by external magnetic force without affecting the integrity of BBB, although the drug release mechanism is yet to be delineated. Further, most ARV drugs have short half-life and thus their prolonged stay in periphery can remarkably reduce the active bioavailability affecting their pharmacokinetics. Most of the nanodrugs/gels reported are shown to be of more than 200 nm in size and therefore cannot penetrate through BBB. Further these drugs or drug carrying nanocarriers are also susceptible to extensive first pass metabolism or uptake by RES system. In spite of significant advances in HAART, the elimination of HIV-1 reservoirs from the CNS remains a formidable task. This is attributed to the inability of antiretroviral therapy (ART) to penetrate BBB after systematic administration. 5′-triphosphate-Azidothymidine (AZTTP), Nelfinavir, Rilpivirine, and Enfuvirtide are among the most deprived ARV drugs in the brain. Therefore, successful approach for direct and speedy delivery of these ARV drugs in sufficient therapeutic levels in the brain could pave a way for the complete eradication of HIV from the brain.
Thus existing studies showed that more than 99% of the nanodrugs are deposited either in liver, lungs or other lymphoid organs before they reach brain. So from a drug delivery point of view, a fast and effective way of delivering and releasing the drugs on demand from the carrier in the brain is very much needed to eradicate HIV reservoir or treat other CNS diseases without hampering the integrity of BBB.